title: Novel CIC point mutations and an exon-spanning, homozygous deletion identified in oligodendroglial tumors by a comprehensive genomic approach including transcriptome sequencing.
abstract: Oligodendroglial tumors form a distinct subgroup of gliomas, characterized by a better response to treatment and prolonged overall survival. Most oligodendrogliomas and also some oligoastrocytomas are characterized by a unique and typical unbalanced translocation, der(1,19), resulting in a 1p/19q co-deletion. Candidate tumor suppressor genes targeted by these losses, CIC on 19q13.2 and FUBP1 on 1p31.1, were only recently discovered. We analyzed 17 oligodendrogliomas and oligoastrocytomas by applying a comprehensive approach consisting of RNA expression analysis, DNA sequencing of CIC, FUBP1, IDH1/2, and array CGH. We confirmed three different genetic subtypes in our samples: i) the "oligodendroglial" subtype with 1p/19q co-deletion in twelve out of 17 tumors; ii) the "astrocytic" subtype in three tumors; iii) the "other" subtype in two tumors. All twelve tumors with the 1p/19q co-deletion carried the most common IDH1 R132H mutation. In seven of these tumors, we found protein-disrupting point mutations in the remaining allele of CIC, four of which are novel. One of these tumors also had a deleterious mutation in FUBP1. Only by integrating RNA expression and array CGH data, were we able to discover an exon-spanning homozygous microdeletion within the remaining allele of CIC in an additional tumor with 1p/19q co-deletion. Therefore we propose that the mutation rate might be underestimated when looking at sequence variants alone. In conclusion, the high frequency and the spectrum of CIC mutations in our 1p/19q-codeleted tumor cohort support the hypothesis that CIC acts as a tumor suppressor in these tumors, whereas FUBP1 might play only a minor role.
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Eisenreich
authors.forename: Khalil
authors.initials: K
authors.lastname: Abou-El-Ardat
authors.forename: Karol
authors.initials: K
authors.lastname: Szafranski
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Campos Valenzuela
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.forename: Janice M
authors.initials: JM
authors.lastname: Nigro
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Gerlach
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.forename: Dietmar
authors.initials: D
authors.lastname: Krex
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
authors.forename: Barbara
authors.initials: B
authors.lastname: Klink
mesh_terms: D000328:Adult; D000483:Alleles; D001254:Astrocytoma / Q000235:genetics; D002872:Chromosome Deletion; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D023281:Genomics; D005910:Glioma / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009837:Oligodendroglioma / Q000235:genetics; D017354:Point Mutation; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA
chemical_list: C498610:CIC protein, human; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D004265:DNA Helicases